Aromatase inhibitors, which suppress the production of estrogens by binding to the aromatase enzyme, have become the hormonal adjuvant treatment of choice for postmenopausal breast cancer. While aromatase inhibitor therapy has been shown to be associated with increased survival, decreased risk of recurrence, and lower risk of contralateral breast cancer compared to tamoxifen, these drugs are also associated with bone loss and an increased risk of fractures, requiring the addition of bone-strengthening medication for many women. Further, about a third of women in clinical trials who are treated with aromatase inhibitors suffer from arthralgias (joint pains) and myalgias (muscle pains) that affect quality of life as well as treatment adherence. Even higher rates of muscle and joint pains have been reported among general clinical populations of women on aromatase inhibitor therapy. The reason for these musculoskeletal symptoms is uncertain but is often attributed to the estrogen depletion. However, all women treated with aromatase inhibitors have low estrogen levels and only a subset of these women develop symptoms. A possible mediating factor that may contribute to these side effects is both the absolute concentrations of circulating ovarian and adrenal androgens as well as their concentrations relative to estrogen levels. Androgens, like estrogen, are bone preserving, and two recent studies of non-cancer populations of women reported associations between lower androgen concentrations and the experiencing of musculoskeletal symptoms. The aim of this study is to determine if androgen levels are associated with the musculoskeletal side effects of aromatase inhibitor therapy. To carry out this aim, we will use blood samples and data that are being collected as part of an ongoing prospective cohort study of women being treated with aromatase inhibitors (n = 80) and a cancer-free comparison group (n = 80). We hypothesize that 1) low serum levels of androgens are associated with musculoskeletal symptoms experienced during aromatase inhibitor treatment independent of estrogen levels, and 2) the associations between androgen levels and musculoskeletal symptoms are stronger among women on aromatase inhibitors, who have an extreme estrogen deficiency, compared to cancer-free postmenopausal women who are not on aromatase inhibitor treatment. PUBLIC HEALTH RELEVANCE: This study will provide information that could guide clinicians and breast cancer patients as to who is most at risk for the musculoskeletal side effects of aromatase inhibitor therapy and, potentially, how to prevent musculoskeletal symptoms, thereby improving quality of life and treatment compliance. In addition, the proposed study would add to the understanding of the relationship between androgens and musculoskeletal symptoms among the general population of postmenopausal women. The importance of conducting research concerning the physiological targets of androgen action was highlighted by a task force recently convened by the Clinical Guidelines Subcommittee of The Endocrine Society.